U.S. patent number 8,163,933 [Application Number 11/956,515] was granted by the patent office on 2012-04-24 for clean, high-yield preparation of s,s and r,s amino acid isosteres.
This patent grant is currently assigned to Ampac Fine Chemicals LLC. Invention is credited to Todd E. Clement, Aslam A. Malik, Hasan Palandoken, James Robinson, III, Joy A. Stringer.
United States Patent |
8,163,933 |
Malik , et al. |
April 24, 2012 |
Clean, high-yield preparation of S,S and R,S amino acid
isosteres
Abstract
The present invention provides compounds and methods that can be
used to convert the intermediate halomethyl ketones (HMKs), e.g.,
chloromethyl ketones, to the corresponding S,S- and
R,S-diastereomers. More particularly, the present invention
provides: (1) reduction methods; (2) inversion methods; and (3)
methods involving the epoxidation of alkenes. Using the various
methods of the present invention, the R,S-epoxide and the
intermediary compounds can be prepared reliably, in high yields and
in high purity.
Inventors: |
Malik; Aslam A. (Cameron Park,
CA), Clement; Todd E. (Folsom, CA), Palandoken; Hasan
(Bowling Green, KY), Robinson, III; James (Sacramento,
CA), Stringer; Joy A. (Folsom, CA) |
Assignee: |
Ampac Fine Chemicals LLC
(Rancho Cordova, CA)
|
Family
ID: |
26830230 |
Appl.
No.: |
11/956,515 |
Filed: |
December 14, 2007 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20090012303 A1 |
Jan 8, 2009 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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11081106 |
Mar 14, 2005 |
7309803 |
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10414541 |
Apr 14, 2003 |
6867311 |
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09321645 |
May 28, 1999 |
6605732 |
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60132278 |
May 3, 1999 |
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Current U.S.
Class: |
548/230 |
Current CPC
Class: |
C07D
263/20 (20130101); C07C 271/22 (20130101); C07C
213/00 (20130101); C07D 303/36 (20130101); C07C
213/00 (20130101); C07C 215/08 (20130101); C07B
2200/09 (20130101) |
Current International
Class: |
C07D
263/00 (20060101) |
Field of
Search: |
;549/512,519
;548/230 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Pegorier et al., Tetrahedron Letters, 36(16), 2753-56, 1995. cited
by examiner .
Barluenga et al., J. Org. Chem., 62:4974-5977 (1997). cited by
other .
Barrish et al., J. Med. Chem., 37(12):1758-1768 (1994). cited by
other .
Beaulieu et al., J. Org. Chem., 62:3440-3448 (1997). cited by other
.
Chen et al., J. Med. Chem., 39:1991-2007 (1996). cited by other
.
Dufour et al., J. Chem. Soc. Perkin Trans. I, 1895-1899 (1986).
cited by other .
Ghosh et al., J. Org. Chem., 62:6080-6082 (1997). cited by other
.
Liu et al., Org. Proc. Res. Dev., 1:45-54 (1997). cited by other
.
Luly et al., J. Org. Chem., 52:1487-1492 (1987). cited by other
.
Parkes et al., J. Org. Chem., 59:3656-3664 (1994). cited by other
.
Raddatz et al., J. Med. Chem., 34(11)3267-3280 (1991). cited by
other .
Shaw, Methods in Enzymology, 11:677-686 (1967). cited by other
.
Shibata et al., Chem. Pharm. Bull., 46(4):733-735 (1998). cited by
other.
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Primary Examiner: Oh; Taylor Victor
Attorney, Agent or Firm: Kilpatrick Townsend & Stockton
LLP
Parent Case Text
CROSS-REFERENCES TO RELATED APPLICATIONS
This application is a division of application Ser. No. 11/081,106,
filed Mar. 14, 2005, which is a division of application Ser. No.
10/414,541, filed Apr. 14, 2003 (now U.S. Pat. No. 6,867,311,
issued Mar. 15, 2005), which is a division of application Ser. No.
09/321,645, filed May 25, 1999 (now U.S. Pat. No. 6,605,732, issued
Aug. 12, 2003), which claims the benefit of U.S. Provisional Patent
Application No. 60/132,278, filed May 3, 1999, which are
incorporated herein by reference in their entirety for all
purposes.
Claims
What is claimed is:
1. A cyclic carbamate compound having the following general
formula: ##STR00041## wherein: R.sup.1 is benzyl; R.sup.2 is a
blocking group selected from Boc, Moc and Cbz; and X.sup.1 is a
leaving group selected from chloro, bromo and fluoro groups.
2. The cyclic carbamate compound in accordance with claim 1,
wherein: R.sup.1 is benzyl; R.sup.2 is Boc; and X.sup.1 is a chloro
or bromo group.
Description
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH OR DEVELOPMENT
Not Applicable
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK
Not Applicable
BACKGROUND OF THE INVENTION
Human immunodeficiency virus (HIV), the causative agent of acquired
immunodeficiency syndrome (AIDS), encodes three enzymes, including
the well-characterized proteinase belonging to the aspartic
proteinase family, the HIV protease. Inhibition of this enzyme has
been regarded as a promising approach for treating AIDS.
Hydroxyethylamine isosteres have been extensively utilized in the
synthesis of potent and selective HIV protease inhibitors. However,
this modern generation of HIV protease inhibitors has created an
interesting challenge for the synthetic organic chemist. Advanced
x-ray structural analysis has allowed for the design of molecules
that fit closely into active sites on enzymes creating very
effective drug molecules. Unfortunately, these molecules, designed
by molecular shape, are often difficult to produce using
conventional chemistry.
The modern generation of HIV inhibitors has structural similarities
in a central three-carbon piece containing two chiral carbons that
link two larger groups on each side (see, e.g., Parkes et al., J.
Org. Chem., 59:3656-3664 (1994). Numerous synthetic routes to these
isosteres have been developed. As illustrated below, a common
strategy to prepare the linking group starts with an amino acid,
such as phenylalanine, to set the chirality of the first carbon.
Then, the linking group is completed by a series of reactions
including a one-carbon homologization during which the old amino
acid carbon is transformed into a hydroxy-functionalized carbon
having the correct chirality. However, the commercial production of
isosteres by this method presents serious challenges, generally
requiring low-temperature organometallic reactions (Ghosh et al.,
J. Org. Chem., 62:6080-6082 (1997) or the use of exotic
reagents.
##STR00001##
A second approach, which is illustrated below, is to convert the
amino acid to an aldehyde and to add the carbon by use of a Wittig
reaction to give an olefin (see, Luly et al., J. Org. Chem.,
52:1487-1492 (1987). The olefin is then epoxidized. Alternatively,
the aldehyde can be reacted with nitromethane, cyanide (see,
Shibata et al., Chem. Pharm. Bull., 46(4):733-735 (1998) or carbene
sources (see, Liu et al., Org. Proc. Res. Dev., 1:45-54 (1997).
Instability and difficulty in preparation of the aldehyde make
these routes undesirable (see, Beaulieu et al., J. Org. Chem.,
62:3440-3448 (1997).
##STR00002##
Other routes that have been published, but not commercialized are
illustrated in FIG. 1.
One of the best reagents that can be used to add a single carbon to
amino acids is diazomethane because it gives high yields and few
side-products. In addition, diazomethane reactions are very clean,
generating only nitrogen as a by-product. HIV inhibitor molecules
need high purity because of the high daily doses required. As such,
diazomethane is an ideal reagent for making high purity compounds.
In spite of the documented hazards of diazomethane, processes have
recently been developed that permit the commercial scale use of
diazomethane to convert amino acids to the homologous chloromethyl
ketones (see, U.S. Pat. No. 5,817,778, which issued to Archibald et
al. on Oct. 6, 1998; and U.S. Pat. No. 5,854,405, which issued to
Archibald et al. on Dec. 29, 1998). FIG. 2 illustrates examples of
HIV protease inhibitors wherein the central linking group can be
synthesized by the commercial use of diazomethane. FIG. 3
illustrates a general reaction scheme that can be used to prepare
the S,S-epoxide compound using diazomethane.
The most useful amino acid isosteres are based on phenylanaline.
The key intermediate in the synthesis of Sequinivir.RTM. (Roche)
and Aprenavir.RTM. (Glaxo Wellcome) is the
(S,S-)N-t-butoxycarbonyl-1,2-epoxy-4-phenyl-3-butanamine. Several
other protease inhibitors, such as those described in Chen et al.
(J. Med. Chem., 39:1991-2007 (1996) or those under development
(e.g., BMS-234475 or BMS-232623), use the diastereomeric (R,S-)
N-t-butoxycarbonyl-1,2-epoxy-4-phenyl-3-butanamine.
Beginning with readily available (L)-phenylanaline, one is able to
manufacture N-t-butoxycarbonyl-1-chloro-2-keto-4-phenylbutanamine
(called "chloroketone" or "CMK") using the methods described in the
literature (see, e.g., Parkes et al., J. Org. Chem., 59:3656-3664
(1994); Shaw, Methods in Enzymology, 11:677-686 (1967); and Dufour
et al., J. Chem. Soc. Perkin Trans. I, 1895-1899 (1986), the
teachings of which are incorporated herein by reference). However,
what are needed in the art are methods that allow one to produce
reliably and in high-yields either diastereomer, i.e., the S,S or
the R,S, from the common chloroketone starting material (see, FIG.
4). Quite surprisingly, the present invention fulfills this and
other needs.
BRIEF SUMMARY OF THE INVENTION
The present invention provides compounds and methods that can be
used to convert the intermediate halomethyl ketones (HMKs), e.g.,
chloromethyl ketones, to the corresponding S,S- and
R,S-diastereomers. It is these chiral centers that determine the
chiral centers in the HIV protease inhibitor and, thus, the
efficacy of the drug. As explained herein, the present invention
provides (1) reduction methods; (2) inversion methods; and (3)
methods for preparing alkenes that, in turn, can undergo
epoxidation reactions to form the desired R,S-epoxide. Using the
various methods of the present invention, the R,S-epoxide and the
intermediary compounds can be prepared reliably, in high yields and
in high purity.
As such, in one embodiment, the present invention provides a method
for selectively preparing an R,S-halomethyl alcohol (R,S-HMA)
compound having the following general formula:
##STR00003## the method comprising: reducing a compound having the
following general formula:
##STR00004## with a nonchelating, bulky reducing agent to form the
R,S-HMA compound. In the above formulae, R.sup.1 is an amino acid
side chain (e.g., a benzyl group, an S-phenyl group, an alkyl group
and a para-nitrobenzene group, etc.); R.sup.2 is a blocking or
protecting group (e.g., Boc, Cbz, Moc, etc.); and X.sup.1 is a
leaving group (e.g., a halo group, such as chloro). In a presently
preferred embodiment, the nonchelating, bulky reducing agent is a
member selected from the group consisting of LATBH and STBH. In
another presently preferred embodiment, the reduction is carried
out in a solvent such as diethyl ether. Once formed, the R,S-HMA
can be reacted with an alkali metal base to form an
R,S-epoxide.
In another embodiment, the present invention provides a method for
preparing an R,S-halomethyl alcohol (R,S-HMA) compound having the
following general formula:
##STR00005## the method comprising: reducing a halomethyl ketone
(HMK) compound having the following general formula:
##STR00006## with a reducing agent selected from the group
consisting of sodium cyanoborohydride, cerium chloride/sodium
borohydride, K-Selectride.RTM., KS-Selectride.RTM. and (+)-Dip
Chloride.TM. to form the R,S-HMA compound. In this method, R.sup.1
is an amino acid side chain; R.sup.2 is a blocking group; and
X.sup.1 is a leaving group. Again, once formed, the R,S-HMA can be
reacted with an alkali metal base to form an R,S-epoxide.
In another aspect, the present invention provides inversion methods
that can be used to selectively prepare the R,S-epoxide. In one
embodiment of the inversion method, R,S-epoxide is prepared by a
four step process. More particularly, in one embodiment of the
inversion method, the present invention provides a method for
preparing an R,S-epoxide having the following general formula:
##STR00007## the method comprising: (a) reducing a halomethyl
ketone (HMK) compound having the following general formula:
##STR00008## with a reducing agent to form an S,S-halomethyl
alcohol (S,S-HMA) compound having the following general
formula:
##STR00009## (b) contacting the S,S-HMA compound of Formula II with
a member selected from the group consisting of arylsulfonyl halides
and alkylsulfonyl halides in the presence of an amine to form an
S,S-halomethyl sulfonyl (S,S-HMS) compound having the following
general formula:
##STR00010## (c) contacting the S,S-HMS compound of Formula III
with an acetate in the presence of a phase transfer catalyst and
water to form an R,S-halomethyl acetate (R,S-HMAc) compound having
the following general formula:
##STR00011## and (d) contacting the R,S-HMAc compound of Formula IV
with an alkali metal base to form the R,S-epoxide. In the above
formulae, R.sup.1 is an amino acid side chain (e.g., a benzyl
group, an S-phenyl group, an alkyl group, a para-nitrobenzene
group, etc.); R.sup.2 is a blocking or protecting group; X.sup.1 is
a leaving group (i.e., a halo group, such as chloro); R.sup.3 is a
functional group including, but not limited to, arylsulfonyls and
alkylsulfonyls (e.g., a mesyl group, a tosyl group, a triflate
group, a nosyl group, etc.); and R.sup.4 is an acyl group derived
from the acetate (e.g., an acetyl group).
In another embodiment of the inversion method, the present
invention provides a method for preparing an R,S-epoxide compound
having the following general formula:
##STR00012## the method comprising: (a) contacting an
S,S-halomethyl sulfonyl (S,S-HMS) compound having the following
general formula:
##STR00013## with a carbamate-forming acetate to form a cyclic
carbamate; and (b) contacting the cyclic carbamate with an alkali
metal base to form the R,S-epoxide. In the above formulae, R.sup.1,
R.sup.2, R.sup.3 and X.sup.1 are as defined above. In a presently
preferred embodiment, the carbamate-forming acetate is sodium
trichloroacetate.
In yet another aspect, the present invention provides a method for
preparing R,S-epoxide by the epoxidation of an alkene. More
particularly, the present invention provides a method for preparing
an alkene having the following general formula:
##STR00014## the method comprising: (a) contacting a compound
having the following general formula:
##STR00015## with a hydrohalo acid to form a compound having the
following general formula:
##STR00016## (b) reducing a compound of Formula II with a reducing
agent to form a compound having the following general formula:
##STR00017## and (c) dehalohydroxylating a compound of Formula III
to form the alkene. In the above formulae, R.sup.1, R.sup.2, and
X.sup.1 are as defined above. Once prepared, the alkene can be
converted to the R,S-epoxide using, for example, m-chloroperbenzoic
acid.
Other features, objects and advantages of the invention and its
preferred embodiments will become apparent from the detailed
description which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates various routes that can be used to prepare an
R,S-epoxide. FIG. 1(A) illustrates a method described by Liu et
al., Org. Proc. Res. Dev., 1:45-54 (1997); and Beaulieu et al., J.
Org. Chem., 62:3441 (1997). FIG. 1(B) illustrates a method
described by Parkes et al., J. Org. Chem., 59:3656-3664 (1994).
FIG. 2 illustrates examples of HIV protease inhibitors where the
central linking group can be synthesized by commercial use of
diazomethane.
FIG. 3 illustrates a general reaction scheme that can be used to
prepare the epoxide compound.
FIG. 4 illustrates the two diastereomers that can be formed from
the common chloroketone starting material, i.e., S,S-epoxide and
R,S-epoxide.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides various compounds and methods that
can be used to prepare both reliable and in high yields either
diastereomer, i.e., the S,S- or the R,S-, from the common
halomethyl ketone (e.g., chloromethyl ketone) starting material.
More particularly, as explained herein in greater detail, the
present invention provides (1) reduction methods; (2) inversion
methods, and (3) methods involving the epoxidation of alkenes.
A. The Reduction Methods
A variety of reducing agents can be used to reduce a halomethyl
ketone (HMK) to a halomethyl alcohol (HMA) (see, Table I). However,
under most conditions, the predominate diastereomer is the
2S,3S-HMA. For instance, reduction of HMK with sodium borohydride
in ethanol (Chen et al., J. Med. Chem., 39:1991-2007 (1996)
produces a 1:4 mixture of R,S:S,S HMA in near quantitative yield.
Moreover, the reduction of HMK with aluminium isopropoxide in
isopropanol can give ratios as high as 1:18 in favor of the
S,S-isomer (see, U.S. Pat. Nos. 5,684,176 and 5,847,144, both of
which issued to Hilpert). Thus, commercial routes to S,S-HMA are
easily achieved.
In contrast, the preparation of the R,S-isomer is much more
difficult. A slight increase in the R,S-HMA:S,S-HMA ratio is
achieved when the reaction solvent, ethanol, is replaced with THF.
Further enhancement in the R,S-HMA:S,S-HMA ratio is obtained when
the reduction is carried out in the presence of CeCl.sub.3
(Barluenga et al., J. Org. Chem., 62:5974 (1997); but even then the
ratio of R,S-HMA:S,S-HMA is <1:1. Other reducing agents, such as
LiAlH4, sodium cyanoborohydride, potassium borohydride, etc., under
a variety of reaction conditions, also fail to provide >1:1
R,S-HMA:S,S-HMA. In fact, a perusal of the literature supports the
observation that S,S-HMA is the preferred isomer using coordinating
reducing reagents, such as borohydrides or aluminium hydrides (see,
U.S. Pat. Nos. 5,684,176 and 5,847,144, both of which issued to
Hilpert).
In contrast to the teachings of both the scientific and patent
literature, it has now been discovered that the reduction of HMK
proceeds with high R,S diastereoselectivity when lithium aluminum
t-butoxyhydride (LATBH) is used as the reducing agent. Quite
surprisingly and in contrast to the findings of the prior art, it
has been found that the reduction of HMK with LATBH in, for
example, diethylether provides a 8:1 mixture of R,S-HMA:S,S-HMA in
97% yield. This high diastereofacial selectivity of the LATBH
reducing agent is unusual since reduction of HMK with similar
reducing agents, such as lithium aluminum hydride or sodium
borohydride, do not favor R,S diastereoselectivity (see, U.S. Pat.
Nos. 5,684,176 and 5,847,144, both of which issued to Hilpert).
TABLE-US-00001 TABLE I HMK Reductions: Reagent(s) Solvent(s) Temp.
Time R,S:S,S Li(OtBu).sub.3AlH Et.sub.2O 0.degree. C. 3 Hrs 8:1
(+)-Dip Chloride .TM.(1.4eq) THF 5.degree. C.-RT 12 Hrs 5:1
K-Selectride .RTM. THF Reflux 2 Hrs 2:1 K-Selectride
.RTM./Ti(OiPr).sub.4 THF 25.degree. C. 30 Min 2:1 KS-Selectride
.RTM. THF RT 2 Hrs 2:1 K-Select./MgBr.sub.2.cndot.OEt.sub.2 THF RT
30 Min 2.6:1 R-Alpine Borane(Conc.) THF Reflux 9 Dys 1:1
L-Selectride .RTM. THF RT 1 Hr 0.9:1 NaBH.sub.4/CeCl.sub.3(anh.)
THF RT 2 Hrs 0.8:1 N-Selectride .RTM. EtOH/THF RT 2 Hrs 0.7:1
NaBH.sub.4/CeCl.sub.3.cndot.7H.sub.2O THF 25.degree. C. 18 Hrs
0.7:1 NaBH.sub.4/EDTA(Na.sub.2.cndot.2H.sub.2O) THF RT 30 Min 0.7:1
NaCNBH.sub.3 THF RT 36 Hrs 0.7:1 (+)-2-Butanol/NaBH.sub.4 THF RT 1
Hr 0.6:1 Cp.sub.2TiBH.sub.4 Glyme RT 30 Min 0.6:1 NaBH.sub.4 THF
25.degree. C. 2 Hrs 0.6:1 NaBH.sub.4/(-)-2-Butanol THF RT 30 Min
0.6:1 NaBH.sub.4/Al(OiPr).sub.4 THF Reflux 2 Hrs 0.6:1
NaBH.sub.4/DiacetoneDglucose THF RT 12 Hrs 0.6:1 NaBH.sub.4/EDTA
THF RT 12 Hrs 0.6:1 NaBH.sub.4/L-Tartaric Acid THF 5.degree. C. 1
Hr 0.6:1 NaBH.sub.4/MgBr.sub.2.cndot.OEt.sub.2 THF RT 1 Hr 0.6:1
BH.sub.3-t-butylamine THF RT 1 Hr 0.5:1 LAH THF 25.degree. C. 1 Hr
0.5:1 LS-Selectride .RTM. THF RT 1 Hr 0.5:1 NaBH.sub.4/D-Tartaric
Acid THF RT 30 Min 0.5:1 (+)-2-Butanol.cndot.BH.sub.3 THF RT 1 Hr
0.4:1 NaBH.sub.4/CaCl.sub.2 MeOH RT 1 Hr 0.4:1 AminoAlcohol Borane
THF 25.degree. C. 12 Hrs 0.3:1 Na(PEG).sub.2BH.sub.2 THF RT 30 Min
0.3:1 THF.cndot.BH.sub.3 EtOH/THF RT 2 Hrs 0.2:1 Al(iOPr).sub.3 IPA
50.degree. C. 3 Dys 0.05:1 NaHB(OCH.sub.3).sub.3 MeOH RT 1 Hr
1:1
As such, in one embodiment, the present invention provides a method
for preparing an R,S-halomethyl alcohol (R,S-HMA) compound having
the following general formula:
##STR00018## the method comprising: reducing a compound having the
following general formula:
##STR00019## with a nonchelating, bulky reducing agent to form the
R,S-HMA compound.
In the above formulae, R.sup.1 is an amino acid side chain. More
particularly, in the above formulae, R.sup.1 is a side chain from
any of the naturally occurring amino acids or amino acid mimetics.
In a preferred embodiment, R.sup.1 is a benzyl group, a substituted
benzyl group, an S-phenyl group, an alkyl group or a
para-nitrobenzene group. In an even more preferred embodiment,
R.sup.1 is a benzyl group. R.sup.2, in the above formulae, is a
blocking or protecting group. It will be readily apparent to those
of skill in the art that suitable -amino blocking groups include,
for example, those known to be useful in the art of stepwise
synthesis of peptides. Included are acyl type protecting groups
(e.g., formyl, trifluoroacetyl, acetyl, etc.), aromatic urethane
type protecting groups (e.g., benzyloxycarbonyl (Cbz), substituted
Cbz, etc.), aliphatic urethane type protecting groups (e.g.,
t-butyloxycarbonyl (Boc), isopropylcarbonyl, cyclohexyloxycarbonyl,
etc.) and alkyl type protecting groups (e.g., benzyl,
triphenylmethyl, etc.). In a presently preferred embodiment, the
blocking group is selected from the group consisting of Boc, Cbz
and Moc (methoxycarbonyl). In the above formulae, X.sup.1 is a
leaving group. Suitable leaving groups will be readily apparent to
those of skill in the art. In a presently preferred embodiment, the
leaving group is a halo group (e.g., Cl, Br, F or I). In an even
more preferred embodiment, X.sup.1 is a chloro or bromo group.
Although many of the compounds disclosed herein contain the
exemplar designation "halo," such as halomethyl ketone (HMK) or
halomethyl alcohol (HMA), it will be readily apparent to those of
skill in the art that other leaving groups can be used in place of
the halo group.
In the above embodiment, the reduction is carried out using a
nonchelating, bulky reducing agent. It has surprisingly been
discovered that nonchelating, bulky reducing agents favor the
S,R-diastereomer. Examples of nonchelating, bulky reducing agents
suitable for use in the methods of the present invention include,
but are not limited to, lithium aluminum t-butoxyhydride (LATBH),
sodium tris-t-butoxyborohydride (STBH). In a presently preferred
embodiment, the nonchelating, bulky reducing agent is LATBH. Once
formed, the R,S-HMA can be reacted with an alkali metal base to
form an R,S-epoxide. An exemplar embodiment of the above method is
illustrated by the following reaction scheme:
Synthesis of R,S-Boc-Epoxide by LATBH Reduction
##STR00020##
In this embodiment, the reduction is preferably carried out in a
solvent. It will be readily apparent to those of skill in the art
that numerous solvents can be used. Exemplar solvents include, but
are not limited, to the following: diethyl ether, THF, MTBE and
mixtures thereof. Quite surprisingly, it has been found that the
reduction of LATBH is dependent on the solvent employed. For
instance, when diethyl ether is used as the solvent, a 8:1 mixture
of R,S-HMA:S,S-HMA is obtained. However, when THF or MTBE is used
as the solvent the ratio of R,S-HMA:S,S-HMA is less than or equal
to about 2:1. Based on these result, it is thought that a variety
of factors, such as steric, solvation and chelation, are
responsible for the high R,S diastereoselectivity observed in LATBH
reduction of HMK. Thus, when LATBH is used as the reducing agent,
diethyl ether is preferably used as the solvent.
LATBH is commercially available as a white powder and is used as a
suspension in diethyl ether. Alternately, LATBH can be prepared in
situ by the reaction of LAH with 3 equivalents of t-butylalcohol in
diethylether and then reacted with HMK. The best solvent, as judged
on basis of R,S-diastereoselectivity, is diethyl ether. However,
the solubility of HMK in diethyl ether is relatively low and a
large amount of diethyl ether is needed to dissolve CMK, thereby
reducing reactor efficiency to some extent. The reactor efficiency
can be improved by either adding HMK as a solid or, alternatively,
as a solution in a secondary solvent (e.g., THF, toluene, ethyl
acetate, etc.) to a suspension of LATBH in diethyl ether. The
reaction rate is not affected, but the diastereoselectivity can be
reduced from 8:1 in pure diethyl ether to about 5:1 with the above
modifications.
In this embodiment, the reduction can be carried out at a
temperature ranging from about -30.degree. C. to about 25.degree.
C. In a presently preferred embodiment, the reduction is carried
out at a temperature ranging from about -5.degree. C. to about
5.degree. C. At lower temperatures, larger amounts of solvent are
needed to maintain homogeneity; whereas at high temperatures,
formation of the epoxide, resulting from intramolecular
cyclization, is observed. At 0.degree. C., the reduction reaction
is rapid and is complete in less than about 30 minutes. It will be
readily apparent to those of skill in the art that the progress of
the reduction reaction can be monitored by, for example, HPLC, and
the reaction is deemed complete when the amount of unreacted HMK is
less than about 1%.
In another embodiment, the present invention provides a method for
preparing an R,S-halomethyl alcohol (R,S-HMA) compound having the
following general formula:
##STR00021## the method comprising: reducing a halomethyl ketone
(HMK) compound having the following general formula:
##STR00022##
with a reducing agent selected from the group consisting of sodium
cyanoborohydride, cerium chloride/sodium borohydride,
K-Selectride.RTM., i.e., potassium tri-sec-butylborohydride,
KS-Selectride.RTM., i.e., potassium trisamylborohydride, and
(+)-Dip Chloride.TM., i.e., (+)-B-chlorodiisopinocampheylborane, to
form the R,S-HMA compound. In this method, R.sup.1 is an amino acid
side chain; R.sup.2 is a blocking group; and X.sup.1 is a leaving
group. It will be readily apparent to those of skill in the art
that the foregoing discussions relating to R.sup.1, R.sup.2 and
X.sup.1 and their preferred embodiments are fully applicable to
this method and, thus, will not be repeated.
As with the previously described method, the reduction is
preferably carried out in a solvent. It will be readily apparent to
those of skill in the art that numerous solvents can be used.
Exemplar solvents include, but are not limited, to the following:
diethyl ether, THF, MTBE and mixtures thereof. In a preferred
embodiment, diethyl ether or THF is employed as the solvent.
Moreover, as with the previously described method, the reduction
can be carried out at a temperature ranging from about -30.degree.
C. to about 25.degree. C. In a presently preferred embodiment, the
reduction is carried out at a temperature ranging from about
-5.degree. C. to about 5.degree. C.
In yet another embodiment, the present invention provides a method
for isolating an R,S-halomethyl alcohol (R,S-HMA) from a mixture of
R,S-HMA and S,S-HMA. S,S-HMA is crystalline and is relatively easy
to purify. In contrast, the R,S-HMA is soluble in most organic
solvents and is difficult to purify by standard purification
techniques, such as recrystallization. Mixtures of R,S-HMA and
S,S-HMA can be separated by column chromatography or by preparative
scale HPLC, but are not practical economically.
It has now been discovered that a mixture of R,S-HMA and S,S-HMA
can be separated on the basis of differential solubility; R,S-HMA
is soluble in hot hexanes, whereas the crystalline diastereomer,
S,S-HMA, is not. As such, the present invention provides a method
for isolating an R,S-halomethyl alcohol (R,S-HMA) from a mixture of
R,S-HMA and S,S-HMA, the method comprising: combining the mixture
of R,S- and S,S-HMAs with hexane and heating to a temperature
ranging from 50.degree. C. to about 60.degree. C. to produce a
hexane extractant; cooling the hexane extractant to a temperature
ranging from about 0.degree. C. to about 10.degree. C., filtering
the hexane extractant to form a first retentate and recovering the
first retentate; combining the first retentate with hexane to form
a hexane solution, heating the hexane solution to a temperature
ranging from about 50.degree. C. to about 60.degree. C., and
cooling the hexane solution to a temperature ranging from about
30.degree. C. to about 40.degree. C. to produce a suspension; and
filtering the suspension to form a second retentate and recovering
the second retentate, wherein the R,S-HMA is present in the second
retentate.
For instance, a crude reaction mixture, consisting of 50-90%
R,S-HMA, 10-50% S,S-HMA and 0-10% Me-ester, was extracted with hot
hexane and the resulting hexane extractant was cooled to 10.degree.
C. and filtered to provide about 94% pure R,S-HMA in 74% yield
(based on HMK); the major contaminant was S,S-HMA (5%). Attempts to
purify the 94% pure material by differential solubility (above
treatment) or by recrystallization from a variety of
solvent/solvent mixtures were not completely successful. However,
it has been determined that the best way to purify the 94% pure
R,S-HMA is to dissolve it in hot hexane (about 60.degree. C.), cool
to about 40.degree. C., and then allowing the mixture to
crystallize at about 35.degree. C. to about 37.degree. C. for at
least 2 h. The crystallized product is then filtered at about
30.degree. C. to about 35.degree. C. to provide about 99.5% pure
R,S-HMA in 83% recovery. Interestingly, it has been found that if
the mixture is cooled to 25.degree. C. and filtered, a mixture
consisting of about 94.5% R,S-HMA and 5.5% S,S-HMA, is obtained.
This result is surprising because S,S-HMA is more crystalline and
is not soluble in hexane, thus suggesting that S,S-HMA, not
R,S-HMA, should be the first to crystallize. Although a variety of
solvent/solvent mixtures, such as methanol, methanol/water,
toluene, dibutyl ether, etc., have been used to purify 94% pure
R,S-HMA, the highest degree of purity/recovery is obtained with the
hot hexane method of the present invention.
Once prepared and purified, the R,S-HMA can be converted into an
R,S-epoxide. As such, in another embodiment, the present invention
provides an A method for preparing an R,S-epoxide compound having
the following general formula:
##STR00023## the method comprising: reducing a haloketone (HMK)
compound having the following general formula:
##STR00024## with a noncoordinating reducing agent to form an
R,S-haloalcohol (R,S-HMA) compound having the following general
formula:
##STR00025## and contacting the R,S-HMA compound of Formula II with
an alkali metal base to form the R,S-epoxide compound. It will be
readily apparent to those of skill in the art that the foregoing
discussions relating to R.sup.1, R.sup.2 and X.sup.1 and their
preferred embodiments are fully applicable to this method and,
thus, will not be repeated. In a presently preferred embodiment,
the noncoordination reducing agent is LATBH and the reduction is
carried out in diethyl ether. In another presently preferred
embodiment, the alkali metal base is selected from the group
consisting of NaOH, KOH, LiOH, NaOCH.sub.3, NaOCH.sub.2CH.sub.3 and
KOtBu. In a further preferred embodiment, KOH is the alkali metal
base used. In another embodiment, calcium hydroxide can be used. B.
The Inversion Method
In one embodiment of the inversion method, R,S-epoxide is prepared
by a four step process illustrated below. More particularly, in one
embodiment of the inversion method, the present invention provides
a method for preparing an R,S-epoxide having the following general
formula:
##STR00026## the method comprising: (a) reducing a haloketone (HMK)
compound having the following general formula:
##STR00027## with a reducing agent to form an S,S-haloalcohol
(S,S-HMA) compound having the following general formula:
##STR00028## (b) contacting the S,S-HMA compound of Formula II with
a member selected from the group consisting of arylsulfonyl halides
and alkylsulfonyl halides in the presence of an amine to form an
S,S-halomethyl sulfonyl (S,S-HMS) compound having the following
general formula:
##STR00029## (c) contacting the S,S-HMS compound of Formula III
with an acetate in the presence of a phase transfer catalyst and
water to form an R,S-halomethyl acetate (R,S-HMAc) compound having
the following general formula:
##STR00030## and (d) contacting the R,S-HMAc compound of Formula IV
with an alkali metal base to form the R,S-epoxide. It will be
readily apparent to those of skill in the art that the foregoing
discussions relating to R.sup.1, R.sup.2 and X.sup.1 and their
preferred embodiments are fully applicable to this method and,
thus, will not be repeated. In the above formulae, R.sup.3 is a
functional group including, but not limited to, arylsulfonyls and
alkylsulfonyls. In a presently preferred embodiment, R.sup.3 is a
member selected from the group consisting of a methylsulfonyl group
(i.e., a mesyl group), a toluenesulfonyl group (i.e., a tosyl
group), a trifluoromethanesulfonyl group (i.e., a triflate group)
and a para-nitrobenzene sulfonyl group (i.e., a nosyl group). It
will be readily apparent to those of skill in the art that other
leaving groups can be used as R.sup.3 in place of the arylsulfonyl
and alkylsulfonyl groups. R.sup.4, in the above formulae, is an
acyl group derived from the acetate. In a presently preferred
embodiment, R.sup.4 is an acetyl group.
In the first step, i.e., step (a), a HMK is reduced with a reducing
agent to form an S,S-HMA. In a preferred embodiment, the reducing
agent is selected from the group consisting of sodium borohydride,
lithium aluminum hydride and sodium cyanoborohydride. In another
preferred embodiment, step (a) is carried out in a solvent.
Suitable solvents include, but are not limited to, ethanol,
methanol, isopropanol, THF, diethyl ether, etc. The reduction can
be carried out at a temperature ranging from about -30.degree. C.
to about room temperature and, more preferably, at about
-20.degree. C. In a presently preferred embodiment, the reduction
step is carried out using sodium borohydride in ethanol to provide
a 6:1 mixture of S,S-HMA:R,S-HMA in 98% yield. The S,S-isomer is
highly crystalline and can be easily purified by recrystallization
to provide >99.8% pure S,S-HMA in 80% yield.
In addition to the foregoing, HMA can also be prepared by Merwin
Pondroff Verley reduction of HMK. In this process, HMK is reacted
with aluminum isopropoxide in refluxing IPA to give S,S-CMA in high
diastereoselectivity. Presumably, under these conditions, the
reduction occurs under chelation control and a mixture of
S,S-HMA:R,S-HMA with ratios as high as 20:1 is obtained (see, U.S.
Pat. Nos. 5,684,176 and 5,847,144, both of which issued to
Hilpert).
In the second step, i.e., step (b), an S,S-HMA is reacted with an
arylsulfonyl halide or an alkylsulfonyl halide in the presence of
an amine to form an S,S-halomethyl sulfonyl (S,S-HMS). Suitable
amines include, but are not limited to, trialkylamines (e.g.,
trimethylamine, triethylamine, etc.), pyridine, 4-dimethylamino
pyridine, etc. In a presently preferred embodiment, the amine is
triethylamine. Step (b) can be carried out in a variety of
different solvents. Exemplar solvents include, but are not limited
to, the following: chlorinated solvents (e.g., methylene chloride,
dichloroethane, chlorotoluene, etc.), aromatic hydrocarbons (e.g.,
toluene, xylenes, etc.), ethyl acetate, ethers (e.g., THF, diethyl
ether, etc.), etc. In another presently preferred embodiment, step
(b) is carried out at a temperature ranging from about -30.degree.
C. to about 100.degree. C. and, more preferably, from about
10.degree. C. to about 70.degree. C.
In a particularly preferred embodiment of step (b), the S,S-HMA is
reacted with methanesulfonyl chloride in toluene in the presence of
an equivalent amount of triethylamine to give the corresponding
2S,3S-CMA Mesylate in 98% yield. The reaction is exothermic and is
best conducted at a temperature ranging from about from about
110.degree. C. to about 70.degree. C. The crude mesylate is
recrystallized from toluene to provide greater than 95% pure
S,S-CMA Mesylate in near quantitative yield. However, in the
preferred process, S,S-CMA Mesylate is not isolated and the
solution of crude S,S-CMA mesylate in toluene is used, without
purification, in the next step, i.e., step (c). Although this
mesylation step can be conducted in a variety of solvents, toluene
is the preferred solvent because it can be used in the next step,
thereby eliminating a solvent exchange step from the process.
In the third step, i.e., step (c), the S,S-HMS is reacted with an
acetate in the presence of a phase transfer catalyst and water to
from a HMAc. Suitable acetates for use in the present method
include, but are not limited to, the following: cesium acetate,
potassium acetate, tetrabutylammonium acetate and sodium acetate.
In a presently preferred embodiment, the acetate is cesium acetate.
A variety of phase transfer catalysts (PTCs) can be used in
carrying out step (c). Exemplar phase transfer catalysts include,
but are not limited to, crown ethers (e.g., 18-crown-6, dibenzo
crown ether, etc.), quaternary ammonium salts and quaternary
phosphonium salts (e.g., TATB, aliq. 336, etc.). In a presently
preferred embodiment, the phase transfer catalyst is a crown ether.
The crown ether 18-crown-6 is particularly preferred because it
allows for the production of R,S-HMAc with least amount of side
product. Moreover, the rate of reaction with 18-crown-6 is much
faster than with any of the other phase transfer catalysts. In
addition, 18-crown-6 can be easily removed from the product by a
simple water wash.
Step (c), i.e., the displacement reaction, can be carried out in a
variety of different solvents. Suitable solvents include, but are
not limited to, hydrocarbons (e.g., hexane, heptane, etc.),
aromatic hydrocarbons (e.g., toluene, xylene, benzene, etc.) and
chlorinated solvents (e.g., CCl.sub.4, dichloroethane,
chlorotoluenes, etc.). In a presently preferred embodiment, toluene
is used as the solvent because it can be used for both steps (b)
and (c), and it can be used as a crystallization solvent for the
R,S-HMAc. In addition, toluene is commercially available from a
variety of sources and can be recycled in high efficiency. The
displacement reaction, i.e., step (c) can be carried out at a
temperature ranging from about 20.degree. C. to about 100.degree.
C. In a presently preferred embodiment, the displacement reaction
is carried out at a temperature ranging from about 20.degree. C. to
about 100.degree. C.
In addition to the foregoing, it has been found that the
displacement reaction is dependent on the amount of water present
in the reaction mixture. Presumably, a small amount of water is
needed to overcome the lattice energy of the metal acetate, thereby
making the nucleophile accessible for the displacement reaction.
However, it has been found that increased amounts of water will
reduce the reactivity of the nucleophile by solvating it. Thus, in
a preferred embodiment, the water is maintained between about 0.5%
and about 10.0% and, more preferably, between about 0.5% and about
5%. Once the displacement reaction is completed, the crude product
can be isolated by crystallization from, for example,
toluene/heptane to give typically greater than 99.5% pure R,S-HMAc
in high yield. Alternately, the R,S-HMAc can be isolated and then
recrystallized from, for example, methanol/water to give pure
R,S-HMAc.
In the final step of the above method, i.e., step (d), the R,S-HMAc
is reacted with an alkali metal base to form the R,S-epoxide. It
has been found that hydrolysis of the R,S-HMAc followed by
subsequent intramolecular ring closure provides the R,S-epoxide in
near quantitative yield. In a presently preferred embodiment, the
alkali metal base is selected from the group consisting of NaOH,
KOH, LiOH, NaOCH.sub.3, NaOCH.sub.2CH.sub.3 and KOtBu. In another
preferred embodiment, step (d) is carried out is a solvent.
Suitable solvents include, but are not limited to, hydrocarbons,
aromatic hydrocarbons, chlorinated solvents and ethers (e.g., THF).
In a presently preferred embodiment, the solvent is a mixture of
toluene and THF.
In a particularly preferred embodiment of step (d), the R,S-HMAc is
reacted with aqueous potassium hydroxide (KOH) in a mixture of THF
and ethanol. Evaporation of solvent followed by titration of the
crude product with hexane afforded the desired R,S-epoxide as a low
melting, white solid.
Since the R,S-epoxide is soluble in most solvents, it is difficult
to purify. In addition, the R,S-epoxide is reactive towards ring
opening reactions and will react with potassium hydroxide in
ethanol to give the corresponding glycol or the ethoxyglcyol side
products. Using this method of the present invention, high purity
R,S-epoxide (>>99.5%) has been prepared by incorporating the
purity at the R,S-HMAc stage and then maintaining the purity by
minimizing side reactions in the final step. Thus, it is important
that the above conversion is achieved in near quantitative yield
and without formation of side products. Again, in a preferred
embodiment of this method, this is accomplished by employing
aqueous KOH. Presumably, in this form, the hydroxide is
nucleophilic enough to allow hydrolysis to occur, but is not
nucleophilic enough to react with the R,S-epoxide and form side
products.
Using this method of the present invention, greater than 99.5% pure
R,S-epoxide can be prepared in 95-97% yields. The R,S-epoxide
prepared by this process can be characterized by NMR, HPLC, TLC and
DSC. Moreover, despite difficulties encountered in the prior art
relating to the purification of the R,S-epoxide, it has now been
discovered that the R,S-epoxide can be purified by
recrystallization from petroleum ether. This is an important
discovery because traditional purification techniques, such as
chromatography, are not applicable due to instability of the
R,S-epoxide towards silica gel and alumina. As such, in a preferred
embodiment, the above method further comprises: purifying the
R,S-epoxide by recrystallization with petroleum ether. An exemplar
embodiment of the above method is illustrated by the following
reaction scheme:
Preparation of the R,S-Epoxide Using One Embodiment of the
Inversion Method
##STR00031##
In another embodiment of the inversion method, the present
invention provides a method for preparing an R,S-epoxide compound
having the following general formula:
##STR00032## the method comprising: (a) contacting an
S,S-halomethyl sulfonyl (S,S-HMS) compound having the following
general formula:
##STR00033## with a carbamate forming acetate to form a cyclic
carbamate having the following general formula:
##STR00034## and (b) contacting the cyclic carbamate with an alkali
metal base to form the R,S-epoxide. It will be readily apparent to
those of skill in the art that the foregoing discussions relating
to R.sup.1, R.sup.2, R.sup.3 and X.sup.1 and their preferred
embodiments are fully applicable to this method and, thus, will not
be repeated. A "carbamate-forming acetate," as used herein, refers
to an acetate that contains a sufficient leaving group. Exemplar
carbamate-forming acetates include, but are not limited to, sodium
trichloroacetate, potassium trichloroacetate, tetrabutylammonium
trichloroacetate, sodium tribromoacetate, potassium tribromoacetate
sodium trifluoroacetate and potassium trifluoroacetate.
As with the previously described methods, step (a) can be carried
out in a variety of solvents, such as hydrocarbons (e.g., hexane,
heptane, etc.), aromatic hydrocarbons (e.g., toluene, xylene,
benzene, etc.) and chlorinated solvents (e.g., CCl.sub.4,
dichloroethane, chlorotoluenes, etc.). In a preferred embodiment,
the solvent is toluene. In step (b) of the above method, the cyclic
carbamate is reacted with an alkali metal base to form the
R,S-epoxide. In a presently preferred embodiment, the alkali metal
base is selected from the group consisting of NaOH, KOH, LiOH,
NaOCH.sub.3, NaOCH.sub.2CH.sub.3 and KOtBu. In another preferred
embodiment, step (b) is carried out in a solvent. Suitable solvents
include, but are not limited to, hydrocarbons, aromatic
hydrocarbons, chlorinated solvents and ethers (e.g., THF). In a
presently preferred embodiment, the solvent is a mixture of THF and
ethanol.
In connection with the above method, the present invention provides
a cyclic carbamate compound having the following general
formula:
##STR00035##
In the above formula, R.sup.1 is an amino acid side chain (e.g.,
benzyl); R.sup.2 is hydrogen or a blocking/protecting group (e.g.,
BOC, MOC, CBZ, etc.); and X.sup.1 is a leaving group (e.g., a
chloro or bromo group). This compound can be readily synthesized
and purified using the methods set forth in Example II.
C. The Alkene Method
In another embodiment, the present invention provides a method for
preparing an alkene having the following general formula:
##STR00036## the method comprising: (a) contacting a compound
having the following general formula:
##STR00037## with a hydrohalo acid to form a compound having the
following general formula:
##STR00038## (b) reducing a compound of Formula II with a reducing
agent to form a compound having the following general formula:
##STR00039## and (c) dehalohydroxylating a compound of Formula III
to form the alkene. It will be readily apparent to those of skill
in the art that the foregoing discussions relating to R.sup.1,
R.sup.2, and X.sup.1 and their preferred embodiments are fully
applicable to this method and, thus, will not be repeated.
In step (a), a compound of Formula I is reacted with a hydrohalo
acid to form a compound of Formula II. Suitable hydrohalo acids
include, but are not limited to, hydrobromic acid, hydrochloric
acid and hydroiodic acid. In a presently preferred embodiment, the
hydrohalo acid is hydrobromic acid or hydrochloric acid. Step (b)
can be carried out using any of a variety of reducing agents. In a
presently preferred embodiment, sodium borohydride is the reducing
agent employed in step (b). Finally, in step (c), compound III is
dehalohydroxylated to form the desired alkene. Suitable
dehalohydroxylating compounds include, but are not limited to, zinc
(0) metals (e.g., zinc dust), nickel metals, zinc mercury amalgan,
etc. Step (c) can be carried out in a number of different solvents.
Suitable solvents include, but are not limited to, methanol,
ethanol, isopropanol, THF, MTBE, toluene, etc. In a presently
preferred embodiment, zinc dust in ethanol is used in step (c).
Once prepared, the alkene can be converted to the R,S-epoxide
using, for example, m-chloroperbenzoic acid as illustrated
below.
In one particularly preferred embodiment of this method, reaction
of the diazoketone (i.e., the compound of Formula I), which is
prepared from phenylalanine using diazomethane, with hydrobromic
acid gives the bromoketone (i.e., the compound of Formula II) in
77% yield. Reduction of the bromoketone with sodium borohydride
under conditions similar to those used for the chloroketone gave
high selectivity for the S,S-bromomethylalcohol (i.e., the compound
of Formula III) over the R,S-diastereomer. The desired S,S-isomer
was isolated in 85% yield after recrystallization (see, Parkes et
al., J. Org. Chem., 59:3656-3664 (1994).
The bromomethylalcohol was dehalohydroxylated to give the olefin
(i.e., the compound of Formula V) by zinc metal in ethanol. Upon
work up, the t-BOC protected S-3-amino-4-phenyl-1-butene was
isolated in 77% yield. Using this method of the present invention,
very pure material was prepared without the problems of
racemization associated with the reaction of the T-BOC protected
S-phenylalanal route. the alkene was converted to the R,S-epoxide
using, for example, a published route using m-chloroperbenzoic
acid. An exemplar embodiment of the above method is illustrated by
the following reaction scheme:
Preparation of the R,S-Expoxide Using the Alkene Method
##STR00040##
The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of noncritical parameters that can be changed or modified
to yield essentially the same results.
EXAMPLES
A. Example I
This example illustrates the preparation of S,S-CMA and R,S-CMA
using the reduction methods of the present invention.
1. Preparation of S,S-CMA by Reduction
A 500 mL, 3-necked round bottom flask was fitted with a condenser,
thermocouple temperature probe, dry nitrogen inlet, and magnetic
stirring. A stirred solution of chloromethylketone (CMK) (19.22 g,
0.0645 mol) and Isopropanol (200 mL) was heated to 50.degree. C.
and aluminum isopropoxide (6.87 g, 0.0337 mol, 1.5 eq) was charged
to the reactor. The reaction mixture was heated at 50.degree. C.
for three hours at which point HPLC analysis indicated 0.4% CMK
remained. After heating for 1 additional hour and cooling to room
temperature, the reaction was quenched with water (200 mL) and
glacial acetic acid (.about.50 mL) to adjust the pH to 4. The
reaction was transferred to a separatory funnel and the organic
solids were extracted into ethyl acetate, resulting in two clear
phases. The phases were split and the organic phase was evaporated
to 18.63 g (97% yield) off-white solid. S,S-Chloromethylalcohol
(S,S-CMA): .sup.1H NMR (CDCl.sub.3): .delta. 1.37 (s, 9H), 2.97 (m,
2H, J=5.1 Hz), 3.20 (br d, 1H), 3.55-3.69 (m, 2H), 3.83-3.93 (m,
2H), 4.59 (br d, 1H, J=6.6 Hz), 7.21-7.34 (m, 5H); HPLC (Short)
t.sub.R 3.84 min=99.51%, 4.66 min=0.49%; HPLC (long) t.sub.R 13.26
min=99.50%, 17.42 min=0.50%.
Proton NMR analysis of final product indicated .about.37:1 ratio of
S,S:R,S Boc-phenylalanine Chloromethylalcohol (CMA), and traces of
acetic acid. HPLC analysis indicated .about.32:1 ratio of S,S:R,S
CMA (95.1% S,S CMA, 3.0% R,S CMA, 0.6% CMK, and 1.3% impurities
from the starting material e.g. methyl ester, boc-phenylalanine).
Further purification was accomplished by recrystallization from
heptane.
2. Sodium Cyanoborohydride Reduction of CMK
To a solution of sodium cyanoborohydride (5.28 g, 84.0 mmol, 1.0
eq) in THF (25 mL) was added a solution of CMK (25.0 g, 84.0 mmol)
in THF (100 mL), followed by addition of AcOH (10 mL) over 0.5 h at
RT. During this addition, internal temperature was never allowed to
rise above 42.degree. C. After 1.5 h, TLC analysis of an aliquot
indicated total consumption of CMK signaling reaction completion.
The reaction mixture was quenched with H.sub.2O (250 mL) and the
resulting white slurry was stirred at ambient temperature for 1 h.
The mixture was extracted with ethyl acetate (500 mL) and then
concentrated on a rotary evaporator to a volume of ca. 300 mL.
Water (100 mL) and the remaining ethyl acetate was removed under
reduced pressure at 45.degree. C. The precipitated product was
filtered, washed with water (200 mL), and dried in a vacuum oven at
45.degree. C./28 inch-Hg for 15 h to give 23.8 g (95% yield) of a
white solid. HPLC analysis revealed that the solid contained a
mixture of 41% R,S-CMA and 59% S,S-CMA.
3. Preparation of R,S-CMA by Reduction with Cerium Chloride/Sodium
Borohydride
A 5000 mL, 3-necked round bottom flask was fitted with mechanical
stirring, Claisen head adapter, condenser, dry nitrogen inlet,
glass enclosed thermocouple temperature probe, and solids addition
funnel, all oven dried at 120.degree. C. and cooled under dry
nitrogen. To a stirred slurry of CMK (200 g, 0.672 mol, 1.0 eq),
cerium chloride heptahydrate (250 g, 0.672 mol, 1.0 eq), and THF
(716 g) was added sodium borohydride (25.5 g, 0.673 mol, 1.0 eq)
portionwise over 70 minutes during which time a 4.5.degree. C.
exotherm was observed. The reaction mixture was stirred for an
additional 5 hours at room temperature, at which time HPLC analysis
indicated that starting material had been consumed. The reaction
was cooled to 2.degree. C. and ethyl acetate (500 mL) was added.
The reaction was quenched with water (1000 mL) at a rate to control
the production of hydrogen gas and maintain at a temperature of
less than 20.degree. C. The pH of the reaction was adjusted to
approximately 6 with glacial acetic acid (18 mL) and additional
ethyl acetate (2500 mL) was added to dissolve the solids. The
reaction was warmed to room temperature and transferred to a 6000
mL separatory funnel. The organic phase was separated, washed with
water and evaporated in vacuo to give 175 g (96% yield) of a white
solid. HPLC analysis of the solid indicated 36% R,S
boc-phenylalanine chloromethylalcohol (CMA) and 60% S,S CMA;
.sup.1H NMR analysis confirmed a 0.6:1 R,S:S,S CMA ratio.
4. Preparation of R,S-CMA by Reduction with LATBH
Lithium tri-t-butoxyaluminohydride (LATBH) (93.87 g, 0.369 mol, 1.1
eq) and anhydrous diethyl ether (500 mL) were placed in a reactor
and cooled to 2.degree. C. A solution of CMK (99.84 g, 0.355 mol)
and anhydrous diethyl ether (2000 mL) was added over 90 min
maintaining an internal temperature of less than 5.degree. C. After
the addition was complete, the mixture was stirred for 30 min at
which point HPLC analysis indicated no starting material remaining.
The reaction was slowly quenched water (1500 mL) and then acetified
with glacial acetic acid (1000 mL) at a rate such the temperature
was below 10.degree. C. The reaction was warmed to ambient and the
organic phase was separated, washed with water and was evaporated
in vacuo to give an orange oil (100.12 g). Hexanes (500 mL) was
added to the flask and evaporated on the rotary evaporator to
remove residual t-butanol and isobutanol; the evaporation yielded
an orange oil/solid (97.34 g, 97% yield).
HPLC and .sup.1H NMR analysis indicated an approximately 6.5:1
ratio of R,S:S,S CMA. The R,S-isomers was purified by extraction
into refluxing hexanes (300 mL), filtration while hot to remove the
less soluble S,S-isomer, and slow cooling overnight. After
filtration and drying, 74.5 g (82.3% yield) of a product that was
92.1% R,S CMA and 5.4% S,S CMA by HPLC and .sup.1H NMR
analysis.
5. Purification of Mixtures of S,S- and R,S-CMA
CMA (170 g of a mixture of 0.6 to 1 isomers) and hexanes (800 g)
were charged to the flask and heated to reflux for 1 hour. The less
soluble isomer mix (90% S,S CMA, 9% R,S CMA) (99.6 g, 58% yield)
was removed by filtration of the hot mixture. The filtrate was
evaporated to 75% volume, cooled and filtered to give the more
soluble isomer mix (94% R,S CMA, 3% S,S CMA) 36.7 g (22% yield)
were removed by cold filtration through a 600 mL coarse, sintered
glass funnel. The residual filtrate was dried in vacuo to give a
yellow oil (18.6 g, 11% yield) containing a mixture of isomers.
A mixture of 32 g of the crude solid (93% R,S-CMA and 6% S,S-CMA)
from the hot hexane recrystallization and hexanes (600 mL) was
heated to 60.degree. C. The resulting solution was slowly allowed
to cool to 53.degree. C. and seeded with R,S-CMA crystals. Further
crystallization was observed at 37.degree. C. at which point
significant amount of white needles had formed in solution. The
internal temperature was maintained between 35-40.degree. C. for
1.5 h, at which point the mixture was hot filtered to provide 25.7
g (80% recovery) of R,S-CMA as white needles. HPLC analyses
revealed that R,S-CMA was 99.8% pure and contained ca. 0.2%
S,S-CMA. Concentration of hexane filtrate on a rotary evaporator
afforded 6.1 g of a white solid which based on HPLC analysis was
found to be consist of 91.9% R,S-CMA and 6.4% S,S-CMA.
R,S-Chloromethylalcohol (R,S-CMA): .sup.1H NMR (CDCl.sub.3):
.delta. 1.36 (s, 9H), 2.94 (m, 2H, J=7.3 Hz), 3.54 (d, 2H, J=4.6
Hz), 3.77 (m, 1H, J=2.1 Hz), 3.94 (m, 1H, J=7.3 Hz), 4.99 (d, 1H,
J=8.8 Hz), 7.24 (br m, 5H); HPLC (Short) t.sub.R 3.87 min=0.21%,
4.69 min=99.79%.
B. Example II
This example illustrates the preparation of R,S-Epoxide using two
different inversion methods. In NMR: Varian 300 MHz; HPLC: Hewlett
Packard 1100, column C18 reverse phase using acetonitrile/water
with phosphate buffer; melting points were measured by DSC
1. Preparation of R,S-Epoxide by the Inversion Route Via an
Acetate
a. Step 1: Mesylation
A 3 L jacketed reactor equipped with a mechanical stirrer, addition
funnel, reflux condenser, temperature probe, and a nitrogen gas
inlet was charged with S,S-CMA (150.3 g, 0.501 mol) and toluene
(1.5 L). The system was flushed with nitrogen and triethylamine (62
g, 0.613 mol) was added. The resulting mixture was treated,
dropwise, with methanesulfonyl chloride (69 g, 0.595 mol). The rate
of addition of methanesulfonyl chloride was maintained so as to
control the reaction temperature below 50.degree. C. When the
addition was complete, the reaction mixture was stirred for 1 h,
sampled and analyzed by HPLC which indicated that the reaction was
complete. The reaction mixture was slowly quenched into 10% aqueous
potassium bicarbonate solution, and the organic phase was separated
and washed with water. The organic layer containing the mesylate
derivative was then dried azeotropically and used without isolation
in the displacement reaction. In order to obtain yield/purity data,
a sample of reaction mixture was withdrawn and stripped off solvent
under reduced pressure to give S,S-CMA mesylate, a pale yellow
solid: mp 117-121.degree. C.; .sup.1H NMR (CDCl.sub.3): .delta.
1.35 (s, 9H), 2.79 (br t, 1H, J=11.1 Hz), 3.04 (dd, 1H, J=14.4, 4.8
Hz), 3.17 (s, 3H), 3.73 (m, 2H, J=4.5 Hz), 4.15 (ddd, 1H, J=5.1,
4.8, 3.6 Hz), 4.69 (br d, 1H, J=6.6 Hz), 5.04 (br s, 1H), 7.20-7.34
(m, 5H); HPLC revealed that the product was 99.7% (area %)
pure.
b. Step 2: Displacement
A second reactor was charged with cesium acetate (241.7 g, 1.125
mol) and 18-crown-6 (33 g, 0.125 mol) in toluene (400 mL) and the
mixture was heated to 70 C. Next, a solution of S,S-CMA mesylate in
toluene was added over 1 h and the resulting mixture was heated at
70.degree. C. for an additional 9 hrs at which time TLC analysis
indicated the reaction was complete. The reactor was cooled to
35.degree. C., and water (1 L) was added. The organic layer was
separated and washed with water and the solvent was evaporated
until the concentration of the product was 20% by weight as
determined by 1H NMR analysis. Heptane (1350 g) was added and the
mixture heated to 55.degree. C. for 30 min, and cooled to ambient
over 1 h. The mixture was then cooled to 5.degree. C., filtered,
and the white solid was dried in vacuo to give 131.5 g (77% yield)
of
(2R,3S)-N-t-butoxycarbonyl-1-chloro-2-acetoxy-4-phenylbutanamine, a
white solid: mp 105-106.degree. C.; .sup.1H NMR (CDCl.sub.3):
.delta. 1.39 (s, 9H), 2.13 (s, 3H), 2.75 (br d, 2H, J=7.5 Hz), 3.56
(br d, 2H, J=6.3 Hz), 4.24 (ddd, 2H, J=7.4, 2.2 Hz), 4.52 and 4.67
(both br d, 1H total, J=9.6 Hz), 5.03-5.12 (m, 1H, J=6.2, 2.1 Hz),
7.17-7.33 (m, 5H); TLC (silica gel, 30% EtOAc/Hexane):
R.sub.f=0.75; HPLC analysis revealed that the product was 99.7%
pure.
c. Step 3: Hydrolysis and Ring Closure
A 1 L flask fitted with a mechanical stirrer, addition funnel,
temperature probe, and a nitrogen inlet was charged with R,S-CMA
Acetate (34.3 g, 100.4 mmol), THF (156 mL), ethanol (90 mL) and
water (30 mL). The mixture was cooled to 0-3.degree. C. and a 43%
aq. KOH solution (13.3 g of 86% potassium hydroxide dissolved in
13.3 mL of water) was added dropwise to the reaction mixture so as
to maintain an internal temperature of <5.degree. C. The
reaction mixture was stirred at 0-3.degree. C. for 1.5 h and then
quenched with 6% aq. sodium biphosphate solution (250 mL); the
reaction temperature was maintained below 110.degree. C. during
quench. Diethyl ether (260 mL) was added and the organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered, and stripped of
solvent under reduced pressure to give a clear oil. Hexane (130 mL)
was added and the resulting mixture was concentrated on a rotary
evaporator till <10% hexane remained and the residue was seeded
with crystals of pure R,S-Epoxide. The mixture was then stored at
room temperature for 16 h and the precipitated solid was collected
by filtration and dried to provide 25.4 g (96%) of the title
compound, a white solid: mp (DSC): 51.56.degree. C.; .sup.1H NMR
(CDCl.sub.3): .delta. 1.39 (s, 9H), 2.59 (s, 1H), 2.70 (dd, 1H,
J=3.9 Hz), 2.91 (m, 2H, J=6.6 Hz), 3.01 (m, 1H, J=3.6 Hz), 4.13 (d,
1H, J=7.8 Hz), 4.49 (d, 1H, J=7.2 Hz), 7.27 (br m, 5H). The purity,
as determined by HPLC analysis, was 99.5%.
d. Alternate Process for Preparation of
2R,3S-Chloromethylacetate
A 4 L jacketed reactor equipped with a mechanical stirrer, reflux
condenser, temperature probe, and a nitrogen gas inlet was charged
with S,S-CMA Mesylate (246.5 g, 0.65 mol) and 18-crown-6 (43.4 g,
0.16 mol), cesium acetate (322.8 g, 1.685.7 mol) and toluene (3.2
L). The resulting mixture was heated at 72.degree. C. for 11 hours,
at which point TLC analysis (silica gel, 30% EtOAc/Hexane)
indicated the starting material had been consumed. The organic
phase was separated and concentrated under reduced pressure to
provide a white solid. The residue was dissolved in ethyl acetate
(1.2 L) and the resulting solution was washed with H.sub.2O
(2.times.550 mL), dried (Na.sub.2SO.sub.4), filtered, and stripped
off solvent under reduced pressure to provide 216 g (97%) of 92%
pure R,S-CMA Acetate. Recrystallization of the crude product from
85:15 methanol/water provided 99.7% pure R,S-CMA Acetate in 57%
yield. The mother liquor was concentrated on rotary evaporator,
treated with water, and chilled to 5.degree. C. to provide an
additional 22 g of 98.2% pure product, thus increasing the total
yield of R,S-CMA Acetate to 76%.
2. Preparation of R,S-Epoxide by the Inversion Route Via
Trichloroacetic Acid
a. Step 1: Preparation of `Cyclic Carbamate`
A 250 mL round-bottom flask equipped with a magnetic stir bar,
reflux condenser, temperature probe, and a nitrogen gas inlet was
charged with 9.98 g (26.4 mmol) of S,S-CMMs, 0.434 g (1.35 mmol) of
tetrabutylammonium bromide (TBAB), 7.46 g (40.2 mmol) of sodium
trichloroacetate, and flushed vigorously with N.sub.2. Toluene (104
mL, 90 g) was added under a steady stream of N.sub.2 and the
resulting slurry was heated to .about.45.degree. C. The reaction
mixture was stirred at 45.degree. C. overnight, at which point TLC
analysis (silica gel, 30% EtOAc/Hexane) indicated the starting
material had been consumed. The toluene phase was transferred from
the reaction vessel into a 500 mL separatory funnel and
EtOAc/H.sub.2O (50 mL/100 mL), used to rinse the reactor, was
combined with the organic layer. After separating the two layers,
the organic layer was washed with H.sub.2O (1.times.100 mL), dried
over Na.sub.2SO.sub.4, filtered, and removed under vacuum. The
resulting crude solid was dried in a vacuum oven (45.degree. C.)
overnight to provide a yield of 92% (7.92 g, 24.3 mmol, .about.90%
pure).
This product was combined with the crude cyclic carbamate (1.67 g,
5.13 mmol) from a previous small scale synthesis (CP078-24) and
crystallized from MeOH/H.sub.2O as follows: 9.59 g of crude product
was dissolved in 43 mL (34 g) of MeOH while heating to 45.degree.
C. To this warm MeOH solution was slowly added 4 mL of H.sub.2O and
the temperature allowed to reach ambient without agitation. Needle
formation was rapid and the flask was cooled to 0-5.degree. C.
prior to filtration, yielding 7.24 g (75.5% recovery) of product
(99.42% pure).
b. Step 2: Preparation of R,S-Epoxide
To a 50 mL round-bottom flask equipped with a magnetic stir bar,
temperature probe, and a nitrogen inlet was added a 43% aqueous KOH
solution (0.73 g soln., 5.82 mmol) and 1.0 g of H.sub.2O. The
contents of the flask were cooled to 0-3.degree. C. with the aid of
an ice-bath. A separate flask was charged with 0.99 g (2.22 mmol)
of the `cyclic carbamate`, 3.2 g of THF, and 1.6 g of EtOH and
agitated to dissolve all solids. The `cyclic carbamate` solution
was added dropwise to the reaction flask via pipette so as to
maintain an internal temperature of <4.degree. C. Once addition
was complete, the reaction was stirred at 0-3.degree. C. for 1
hour, at which point the reaction was quenched by addition of a
sodium biphosphate solution (0.448 g NaH.sub.2PO.sub.4, 6.8 g
H.sub.2O). The reaction quench was conducted at such a rate as to
keep the internal temperature <10.degree. C. (Note: The reaction
was analyzed for completion via TLC after a 30 min. post-stir and
found to contain the desired epoxide.) The cloudy reaction mixture
was diluted with 10 mL of Et.sub.2O and the layers were separated.
The clear organic layer was dried over Na.sub.2SO.sub.4, filtered,
and the solvent was removed under vacuum to afford a clear oil (0.8
g).
The crude product was taken up in 20% EtOAc/hexanes (due to
solubility problems in desired eluent) and purified via column
chromatography (silica gel, 10% EtOAc/hexanes). R,S-epoxide, as
well as a small amount of a nonpolar impurity, were collected prior
to running a gradient to 50% EtOAc/hexanes to collect the deblocked
impurity. The two fractions were evaporated of solvent to obtain
clear oils: R,S-epoxide: 0.444 g (solidified under vacuum; HPLC:
.about.90%). The identity of the R,S-epoxide was confirmed by
.sup.1H NMR, HPLC, and TLC.
c. Mechanistic Discussion
Without intending to be bound by any theory, it is thought that the
reaction occurs through the following mechanism. Attack of a
trichloroacetate anion on the secondary mesylate in an SN.sub.2
fashion inverts the stereochemistry and provides the intermediate
R,S-chloromethyltrichloroacetate (R,S-CMAcCl.sub.3). Due to the
excellent leaving group ability of: CCl.sub.3 (trichlorocarbene),
nucleophilic attack of the carbamate nitrogen on the acetate
carbonyl and subsequent (or concurrent) loss of a proton provides
the cyclic carbamate. It is thought that treatment of this species
with aqueous base favors reaction of the hydroxide at the cyclic
carbonyl, possibly due to the added benefit of relieving the ring
strain of the molecule, resulting in the expected epoxide
(55-60%).
C. Example III
This example illustrates the preparation of the R,S-epoxide by the
epoxidation of an alkene.
1. Preparation of Bromomethyl Ketone (BMK)
A solution of diazomethyl ketone (DMK) in ethyl acetate/diethyl
ether (16.8 g solution, 1 g DMK, 3.5 mmol) was cooled to 5.degree.
C. and treated dropwise with a solution of hydrobromic acid (1.8 g,
10.6 mmol); the reaction temperature was maintained below
10.degree. C. during the addition. The resulting mixture was
stirred at 0-5.degree. C. for 2 hours and quenched with water (20
mL). The organic layer was separated and washed with water
(3.times.20 mL) until the pH of the final water wash was >6. The
organic layer was concentrated on a rotary evaporator to give 0.92
g (77%) of an off-white solid. The product purity, as determined by
HPLC, was 91%. .sup.1H NMR-(S,S-BMK; CDCl.sub.3)): .delta. 1.41 (s,
9H), 3.07 (m, 2H, J=6.6 Hz), 3.94 (m, 2H, J=16.2 Hz), 4.72 (q, 1H,
J=7.2 Hz), 5.07 (d, 1H, J=7.5 Hz), 7.20-7.31 (br m, 5H).
2. Preparation of Bromomethylalcohol (BMA)
A mixture of bromomethylketone (20.3 g, 59.3 mmol), ethyl acetate
(160 mL), and ethanol (240 mL) was cooled to -30.degree. C. and
treated, dropwise, with a slurry of sodium borohydride (1.16 g,
30.7 mmol) in ethanol (80 mL). The reaction mixture was stirred at
-30.degree. C. for 30 min. and quenched with acetic acid (4 mL);
the reaction temperature was maintained below -20.degree. C. during
the quench. The reaction mixture was then warmed to room
temperature and treated with water (100 mL) and ethyl acetate (150
mL). The layers were separated and the organic layer was filtered
to give 2.8 g of 96.6% pure S,S-BMA. The organic layer was then
dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give
14.2 g of a mixture consisting of 85% S,S-BMA, 6% R,S-BMA, and 5%
methyl ester. .sup.1H NMR (S,S-BMA; CDCl.sub.3): .delta. 1.36 (s,
9H), 2.98 (br m, 2H, J=4.5 Hz), 3.46 (br m, 1H, J=9 Hz), 3.54 (br
m, 1H), 3.86 (br s, 2H), 4.56 (br s, 1H), 7.20-7.31 (m, 5H); HPLC
(Short) t.sub.R 2.29 min=0.07%, 3.88 min=2.68%, 4.29 min=96.61%,
5.25 min=0.64%.
3. Preparation of BOC-Alkene
A mixture of crude BMA (12.1 g, 35.2 mmol) prepared above and
ethanol (240 mL) was heated to reflux and zinc dust (22.4 g, 343
mmol) was added. The resulting mixture was refluxed for 5 h, at
which time TLC analysis (silica gel, 30% EtOAc/Hexane) indicated
the starting material had been consumed. The reaction mixture was
cooled to room temperature, unreacted zinc dust was removed by
filtration, and the filtrate was concentrated in vacuo to give an
oil. This oil was dissolved in ethyl acetate (100 mL) and washed
with 2% aqueous acetic acid (50 mL). The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and evaporated to
give 7.5 g of crude product, an oil; this oil solidified on
standing at room temperature to give a white solid. The solid was
dissolved in methylene chloride (50 mL) and the solution was
filtered through 10 g of silica gel. Evaporation of the solvent
gave 6.0 g (77% yield of the desired olefin. HPLC analysis showed
the olefin was >99% pure. BOC-Alkene: .sup.1H NMR (CDCl.sub.3):
.delta. 1.40 (s, 9H), 2.83 (br d, 2H, J=6.6 Hz), 4.43 (br s, 2H),
4.56 (br s, 2H), 5.06-5.13 (m, 2H, J=17.4, 10.5, 1.2 Hz), 5.8 (ddd,
2H, J=17.1, 10.5, 5.4 Hz), 7.20-7.31 (m, 5H); IR (thin film): .nu.
3359 (NH), 1686 (CO), 1645 (alkene); HPLC (Short) t.sub.R 3.87
min=0.65%, 4.01 min=0.04%, 4.69 min=0.19%, 8.38 min=99.12%; MS, m/e
MH.sup.+ 248.1661.
4. R,S-Epoxide by Alkene Route
A mixture of BOC-alkene (0.498 g, 2.02 mmol), meta-chloroperbenzoic
acid (1.93 g, 8.1 mmol) and dichloromethane (22 mL) was stirred at
ambient temperature for 3 h at which time HPLC analysis indicated
the starting material had been consumed. The reaction mixture was
quenched with aqueous 10% Na.sub.2SO.sub.3 (60 mL), and diluted
with diethyl ether. The organic layer was washed with cold
saturated Na.sub.2CO.sub.3 (60 mL), brine (60 mL), dried over
Na.sub.2SO.sub.4, and the solvent evaporated to provide a clear oil
that solidified on standing. A white solid (0.49 g, 1.86 mmol) was
isolated in 92% yield and was shown to be a 5.2:1 mixture of R,S-
and S,S-epoxide, respectively (HPLC, 96.5% pure combined). Analysis
of the product mixture by proton NMR spectroscopy indicated an
approximate 5.7:1 ratio of diasteriomeric epoxides and no alkene
starting material.
It is to be understood that the above description is intended to be
illustrative and not restrictive. Many embodiments will be apparent
to those of skill in the art upon reading the above description.
The scope of the invention should, therefore, be determined not
with reference to the above description, but should instead be
determined with reference to the appended claims, along with the
full scope of equivalents to which such claims are entitled. The
disclosures of all articles and references, including patent
applications and publications, are incorporated herein by reference
for all purposes.
* * * * *